Project Summary: Autistic spectrum disorder (ASD) is a neurodevelopmental condition defined by variable degrees of impairment in socialization, language, and behavior which affects one out of every 150 children. The most severe form is autism. Symptoms present early in childhood and cause significant lifelong disability. Autism has a strong hereditary basis but the genetics are complex, involving contributions from multiple genes as well as environmental factors. Understanding the etiology of this disease is important, both for improving clinical treatments and diagnostic testing, as well as for understanding human neurodevelopment. In this regard, the study of rare mutations which lead to autism becomes a powerful means of identifying critical neurodevelopmental pathways and identifying their components. One intriguing candidate is the Fox-1 gene (also called A2BP1). Several lines of evidence suggest that Fox-1 is an important neurodevelopmental factor. Fox-1 is a neuron-specific regulator of alternative splicing that appears to play a significant role in gene expression in both human and mouse brain. Furthermore, four patients have been identified with mutations in the Fox-1 gene and features of ASD, including one with a clinical diagnosis of autism. We hypothesize that Fox-1 plays a key role in gene expression during early human neurodevelopment and that disruptions can lead to autistic spectrum disorder. To verify this, we will 1) identify genes whose alternative splicing is regulated by Fox-1 in human neuronal cells using a splicing microarray platform. Next we will 2) extend these findings to neurodevelopment by identifying Fox-1-dependent alternative splicing changes that occur during the differentiation of human neuronal cells to neurons. Finally, we will 3) characterize the role of these Fox-1 target genes in neurodevelopment using in situ hybridization in human fetal brain and, as part of a collaborative project, correlate this to mouse development. This project will improve our understanding of gene regulation during neurodevelopment and stimulate further studies of autism and ASD. The candidate has a strong interest in neurodevelopmental and neurodegenerative disease as well as a solid background in molecular biology and RNA processing which will be strengthened by the experience in human genetics, functional genomics, and bioinformatics proposed here. The site is a productive academic institution, with an extensive neuroscience community, committed to the career development of the candidate. The mentor is a leader in the field of autism research and has an active neurogenetics laboratory with all the tools for genetic and molecular research. Overall, these resources provide the optimum environment for the candidate to transition into an independent role as a scientific investigator. Relevance: Autistic spectrum disorder is being recognized as a major US health concern. It is estimated that up to 500,000 children experience some form of this condition, with perhaps one-quarter having clinical autism. Autism and ASD can have a devastating impact on patients and their families as the condition leads to significant life-long disability. The studies proposed here, examining the role a brain-specific regulator of gene expression in neurodevelopment, will extend our knowledge of what can cause ASD and may ultimately help to better treat, prevent, or someday even cure autism.